mechanismshave been viewed as protection against microorganisms. We now know that
these mechanisms also play major roles in other areas such as allergy,
autoimmune disease, cancer, and organ transplant rejection.In this section we will survey the major
defense mechanisms and see how they function in the above mentioned areas.

B.Non‑specific defense ‑ Defense
mechanisms are usually considered

to beeither specific (aimed at a specific organism or substance) and non‑specific
(triggered by a large number of different agents). The non‑specific
mechanisms constitute the first two lines of body defense.

l.First line of defense ‑ Skin and mucous
membranes ‑ These

form a physical barrier between the
internal body and the external environment.The skin guards the external body while the mucous membranes line and
protect the openings to the body. In addition to the barrier function, the skin
produces antimicrobial substances and generally provides an environment which
is not conducive to the growth of microorganisms. The stomach produces large
quantities of HCL which also serves as an antimicrobial agent.

2.Second
line of defense ‑ These are mechanisms which are

triggeredwhen the first line as not proved effective.These include the following.

a.Phagocytosis ‑ This is the ingestion and destruction of

organisms, foreign material, and
diseased and dying

tissues by the phagocytic cells of
the body.As previously discussed there
are two principal classes of phagocytic cells.

(l)Granulocytes ‑ These are the white cells that are

found principally in the
blood.PMN's can leave the blood and
move into the tissues. Mast cells, which are found throughout the
connective tissues and usually associated with allergic responses have also
been shown to ingest and destroy a wide range of bacteria.

(2)Agranulocytes (Mononuclear cells) ‑ These are themonocytes and macrophages.They are found throughout the connective
tissues of the body and lining various lymph and vascular channels.Collectively these cells constitute a
cleansing and surveillance system referred to as the Reticuloendothelial system
or RE system. More recently this system has been renamed the Mononuclear
phagocytic system (MPS).

b.Inflammation ‑ This is a response of the body to any

irritating agent.The overall function is to remove the

source of irritation, prevent the
spread of infection if a microbe is present,and repair the damage which has been

done.The components of the process are as follows.

(l)Hyperemia ‑ This is increased blood flow to the

point of irritation.It is brought about by the dilation of the
blood vessels supplying the irritated area.This dilation is brought about by chemical substances released by
damaged tissues, Mast cells (cells found in connective tissues which have
chemical contents similar to basophils), and basophils.If the inflammatory response is occurring
near the surface of the body the hyperemia will result in redness (rubor)
and warmth (calor) two of the cardinal signs of inflammation.Increased blood flow to the area permits the
mobilization of white cells and other defensive agents carried by the blood.

(2)Swelling (tumor) ‑ This is the third cardinal sign

of inflammation and is due to the
accumulation of

tissue fluid (edema).This increased tissue fluid is due to
increased permeability of the capillary blood vessels.The increased permeability is brought about
by the chemical mediators released by the same cells that caused
hyperemia.Increased fluid in the area
brings additional nutrients and other vital defense substances.Swelling causes compression of the nerve
endings which results in pain (dolor) the fourth cardinal sign of inflammation.

(3)Pus formation ‑Injured cells release substances

that attract phagocytic cells,
especially neutrophils. These cells congregate at the site of infection where
they ingest microorganisms, dead and dying cells, and

other debris.The combination of tissue fluid, white

cells, and cellular debris
constitute pus.

(4)Defensive fibrin ‑ The excess fluid from the

circulation brings with it the
clotting protein fibrinogen.It
formsa fibrin meshwork around the
infected area.This prevents the spread
of the infection from the immediate area.If the inflammatory response fails to fully clear the area of debris,
then fiber forming cells contribute collagenous fibers which form a capsule
that walls off the distressedarea.A closed fibrous sac such
as this is termed an

abscess.

(5)Repair ‑ Eventually all of the distress is removed

and the dead cells
phagocytized.Abscesses located at the
surface of the body rupture and drain to the

outside.Abscessed deep in the body must be
reabsorbed by the body.The cavity left
fills up with scar tissue and the process is complete.

(6)Chemical mediators of inflammation ‑ As has beendiscussed, the processes involved in
inflammation are mediated by chemicalsubstances.These substancesinclude
the following.

defense including specific
immunity.Active complement components
can mediate virtually every aspect of theinflammatory response.The
activation of complement can be a part of specific immunity or it can be
specific.The non‑specific
activation usually begins with a protein called properdin which can attach to
molecules found on many bacteria (but not body cells).

(d)Prostaglandins ‑ These are local hormones which are related to
fatty acids.They can causevasodilation, pain, and
fever.

(e)
Leukotrienes ‑These are
substances produced byleukocytes.They are chemically
similar toprostaglandins.They can cause increasedpermeability, adherence of leukocytes to thelining of small vessels, and they
are chemotacticfor neutrophils.

(f) B-defensins  These
are broad-spectrum antibioticlike substances epithelial mucosal cells that
linethe hollow
organs.At inflammatory sites
wherethese
epithelium has been breached, large amountsof these are released to control bacteria
andfungi.

c.Natural
Killer (NK) cells ‑ These are large granular

lymphocytes.They are non‑specific and kill both
tumor cellsand virus invaded
cells.Such cells usually have altered
membranes antigens that NK cells recognize.NK contact the target cells and destroy their membranes by releasing
substances known as perforins.NK cells may be our primary defense against cancer, especially in the
early stages before an immune response against the tumor cells has developed.
The constant monitoring of body cells by NK cells is termed immunological
surveillance.

d.Interferon
‑ This is a protein produced by cells when invaded by viruses.It does not protect the invaded cell, but is
absorbed by adjacent cells where it stimulates the synthesis of an antiviral
protein which protects those cells. In addition, interferons stimulate the
activity of macrophages and NK cells.

by lymphocytes ). This
interferon functions in specific immunity and will be discussed more completely
later.

(2)Interferon also has anti‑cancer activity.During

recentyears interferon genes have been cloned into

bacteria so that large quantities
are now available. Interferon has been
used as an anticancer agent. It has not show activity against themore common cancers such as breast, lung,
and colon, butit does have good affect
on rarer forms. Recently, new subtypes of interferon have been discovered and
there is hope that some of these may have more powerful anticancer properties.

(3)There is also hope that interferon may prove to be a

goodantiviral drug.The
results are mixed, and many side effects have been found.

e.Complement
- This is a series of plasma proteins that circulate in an inactive stateComplement when activated becomes a major
mechanism for destroying foreign substances in the body.Complement functions in both non-specific
defense as well as in specific immunity.It will be considered in more detail along with specific immunity.

f.Fever - This is an increase in body
temperature that usually accompanies infection.Current evidence indicates that fever is a protective response of
the body to infection, and many infectious organisms cannot grow well at
elevated body temperatures. Many bacteria require large amounts of iron and
zinc to multiply.Fever causes the
liver and spleen to sequester these elements, reducing the supply available to
the bacteria. Substances called pyrogens
are responsible for fever.Pyrogens
are substances producedby leukocytes
and macrophages which have been exposed to microgoranisms.

C.
Specific resistance ‑
Third line of defense ‑ This is immunity,

andas thename implies is
specifically targeted.It is composed
of cells and molecules which recognize and destroy the offending agent. The
principal cells of the immune response are the lymphocytes and macrophages.

provokean immune response,either HMI
or CMI or both.It is antigens to which
the immune system responds. Chemically,antigens are usually eitherproteinsor complex
carbohydrates. In order to be antigenic, a molecule must possess a large degree
of complexity.

a.Haptens
- These are small molecules which are ordinarily not antigenic.However, sometime in the body they may
combine with proteins and the combination then does become antigenic.After this occurs, the hapten by itself is
capable of provoking an immune response.This is the basis for many drug allergies.

3.Antigen
receptors -Every lymphocyte has a
unique molecule on its membrane surface that functions as the antigen
receptor.These receptors have a three
dimensional shape that will allow them to combine with only one particular
antigen, and it is the recognition of this antigen that is the basis of the
immune response.At there are literally
millions of different shaped antigens there must also be millions of different
lymphocytes each with its own antigen receptor.How all of these different antigen receptors originate will be
discussed in more detail later.

4.Cellular basisof immunity ‑
There are three functional cell

categories which play a role in specific
immunity.They are as follows.

a.Antigen
presenting cells - These are macrophages, B lymphocytes, and certain skin cells
known as dendritic cells.These
cells encounter the antigen for the

first time.They process the antigen and display
components of the antigen on their own cell membrane so that other key cells in
the immune response can recognize it and respond accordingly.

b.T ‑ lymphocytes (T‑cells) ‑ These are lymphocytes
which

have been processed by the thymus
gland.There is a hormone (or aseriesof hormones) termed thymosin which is produced by the thymus gland.This hormone induces the maturation of immature
lymphocytes from the bone marrowintomature T‑cells.Fully80% of the circulatinglymphocytes are T‑cells.T‑cells all appear identicalbutcanbeshow tofallintoseveraldifferent
functionalcategories.Each subclass can be identified bythereceptors(molecules)foundonthesurfaceof its
membrane.Two of the major receptors
are designated CD4 and CD8.The major subclasses of T‑cells are as follows.

(l)Helper T cells (T4 or TH) ‑ This is the
primary regulatory cell of the immune system.It is ultimately responsible for recognizing the antigen displayed by
the macrophage and then signaling for an appropriate immune response.It may be thought of as the commander and
chief of the immune system.This is the
cell that the AIDS virus destroys.There are two subpopulations of helper T cells.

(a)TH1 - This subpopulation of helper T-cells release a
variety of chemical substances which recruit macrophages and stimulate TC
cells to proliferate. They function in cell mediated responses.

(b)TH2
 These direct migration of eosinophils and basophils to the site of
distress. They also fight parasitic infections of the gut.

Both populations help B cells
to initiate antibodyresponses.

(2)Cytotoxic T cells (T8) ‑ These cells have the
ability to make contact with other cells and destroy them.They seem to be especially effective against
virus infected cells and cancer cells.

(3)T
suppressor cells (T8) ‑ These cells also have a
regulatoryrole but it is directed
toward suppression of an immune response.These cellsplay a role interminating immune responses that have run
their course. They also may play a role in self tolerance.

(4) TDH  These are
delayed hypersensitivity cells.Theyexhibit
both CD4 and CD8 markers and play a role incertain
allergic responses.

c.B‑lymphocytes
(B‑cells) ‑ These are cells that produce antibody. They are
recruited by T‑helper cells.They
have receptors on their membrane that interact with antigen.When stimulated by antigen and helper
T‑cells, they undergo rapid mitosis to form a clone of large lymphocytes
termed plasma cells.These are
active antibody producing cells.They
produce antibody which is specific for the antigen which stimulated the B‑cell,
that is, antibody which has the same shape as does the antigen receptor on the
B-cell. B‑cells appear identical to T‑cells and can only be
separatedbased upon their membrane
receptors.

d.Memory
cells ‑ Both T and B lymphocytes produce memory cells that exist for long
periods of time and remember the antigen.If the antigen makes a subsequent appearance, these memory cells
immediately initiate an immune response. Consequently an intense immune
response can be mounted immediately, destroying the antigen carrying organisms
before they can establish an infection.This is why we are usually immune of a disease that we have had
previously.

e.Summary
‑ The following is a summary of the cellular events and interactions that
occur during the immune response.

(l)Antigen reacts with receptors found on the surface of B lymphocytes
and/or cytotoxic T lymphocytes.The
antigen must also be processed by an APC and presented to a T‑helper
cell.

(2)The now activated T‑helper cell divides to form a colony of
cells which are sensitive to that particular antigen. The helper cells now
release chemical agents which activate B‑cells and/or cytotoxic T‑cells.These cells now proliferate and initiate an
immune response against the antigen. The activated helper T cells only interact
with B-cells and cytotoxic T-cells which have been activated by the same
antigen.

(3)The B‑cells which have been activated produce antibody which
binds with the antigen thereby altering it in some fashion.If the antigen is attached to cells, or
inside of cells, cytotoxic T cells can attach to these cells and destroy them.

(4)Once the immune response has run its course and the antigen has been
cleared, T‑suppressor cells will bring a halt to the various immune
reactions and thereby prevent an over reaction which could harm the body.

(5)A population of memory cells, both B and T, willcontinue to circulate.When an antigen is seen for the first time,
there may be only four or five lymphocytes which have receptors that will fit
it and become activated.These cells
must proliferate to reach sufficient numbers to be effective.For this reason, initially an immune
response may take 5 to 10 days to become powerful enough to clear the
antigen.However, following antigen
clearing, thousands of memory cells for that antigen will remain.If they ever meet the antigenagain they will be present in sufficient
numbers to provoke an immediate response thereby destroying the antigen before
disease can result.

cellular interactions described
previously rely on precise recognition and communicationbetween the various cells of the immune
response system.

a.Antigen
recognition ‑ The cells of the immune response system must be able to
recognize foreign antigen and each other. as all other body cells.The basis of this recognition is a set of
self antigens found on the surface of the cells.These are referred to as the MHC (major histocompatibility
complex) antigens or the HLA(human leukocyte antigens).These surface antigens are all genetically controlled
and serve as identification markers for antigen presentation and
recognition.Only identical twins will
have absolutely identical MHCs. There are two major classes.

(l)ClassI‑ These antigens are foundonall

nucleatedcells in the body.

(2)ClassII‑These are found onlyon antigen
presenting cells.

Both
classes are involved in antigen presentation. Antigen must be combined with
these MHC self antigens in order to be recognized.The origin of the antigen determines which class of MHC will be
involved.

(1)Exogenous
(outside) antigens - These must be combined with class II cell antigens.The APC processes the exogenous antigen and
then combines parts of it with its own MHC II antigens which are then read by
the helper T cell.This type of
presentation can turn on both HMI and CMI.

(2)Endogenous
(inside) antigen - This antigen comes from inside the body cell, usually from a
virus infection or a cancer.This can
be combined with MHC I proteins found on the surface of any nucleated cell and
presented to cytotoxic T cells.This
type of presentation can affect only CMI. It is primarily a defense against our
own body cells that have become diseased and potentially threaten the other cells.Therefore, any cell can call in the defense
of cytotoxic T cells.Note that for the
cytotoxic T cells to become activate and proliferate, they must receive a
second signal from a helper T cell.This means that the antigen in question must also be processed by an
APC.

b.Costimulation
-In order for a T cell to become
activated and respond to an antigen requires more than the presence and
recognition of the antigen itself.There must always be a second signal or a costimulator.This costimulator represents a second
binding site on the presenting cell that must attach to the T cell.The costimulator serves as a fail safe
mechanism to prevent T cells from attacking normal cells.A good analogy for antigen and
costimulation is the activation of a car.The first signal is the key in the ignition (antigen), but in order to
have the car to move it must be put into gear (costimulation). Sometimes the
costimulator is found on the APC, a protein molecule that is produced during
the initial ingestion of antigen.At
other times it is a polypeptide released by a macrophage or T cell known as a
cytokine.

(1)Anergy
- This represents a prolonged state of inactivity that an immune cell undergoes
once it has combined with antigen but not received proper costimulation.Anergy can result in the loss of ability to
respond to the bound antigen by the immune system.

c.Communication ‑ cytokines ‑ The cells of the immune

system have receptors on their
surfaces that respond to antigen and otherreceptorsthat respond tochemicalsignals.Thesesignalsareproteinsreleased by various white cellsandare termed cytokines.Those
released from macrophages are known as monokines while those released
from lymphocytes are termed lymphokines.Atthis point over 30
have been discovered.Some of the
better knowncytokines and their
functionsarelisted

below.

Cytokine

Origin

Target

Action

Interleukin-l
(Il-1)

monocytes
and macrophages

TH
cell, B cell:

activation
and proliferation: promotes fever and inflammation

Interleukin-2
(Il-2)

TH
cells

TH
and TC cells and B cells

growth
and proliferation: activates NK cells

Interleukin-3
(Il-3)

TH
cells

hematopoietic
stem cells and mast cells

growth
and proliferation

Interleukin-4
(Il-4)

TH
cells

B
cells

Costimulates
activated B cells: stimulates secretion of IgE

Interleukin-5
(Il-5)

TH
cells

B
cells

Costimulates
B activated B cells: IgA secretion

Interleukin-6

(Il-6)

TH
cells

B
cells

Converts
B cells into plasma cells

Gamma
interferon

TH
cells

many

many

Colony
stimulating factors (CSF)

TH
cells and macrophages

hemopoietic
tissue

proliferation
of granulocytes

Tumor
necrosis factor (TNF)

monocytes
and macrophages

tumor
cells

destruction

Macrophage
chemotactic factor (MCF)

TH
cells

macrophages

attracts
to site of CMI reactions

Macrophage
inhibiting factor (MIF)

TH
cells

macrophages

inhibits
movement from area of CMI reactions

Perforin

TC
cells and

NK
cells

infected
body cells

destruction
of

target
cell

membrane

d.An example of the recognition and communication that goes

on among the immune cells would be
as follows.

(l)A macrophage engulfs an invading organism.Themacrophage
digests the antigen and combines fragments of it with its MHC II self antigen.

(2)A helper T cell with an appropriately shaped antigen receptor
attaches to the macrophage by recognizing the MHC II-antigen combination on the
macrophage's membrane.After
costimulation has occurred, the macrophage releases Il-1 which stimulates
division of the helper T cell.

(3)The activated helper T‑cell produces Il‑2 whichis self stimulatory and causes the
helper T cell to grow and divide.Il-2
can also cause proliferation and cytotoxic T cells that have been presented
antigen.

response until the invading
organism is overwhelmed by sheer strength of numbers.

6.Humoral mediated immunity ‑This is immunity which is

mediated by antibodies produced by B‑cells.A more recent term for antibody is
immunoglobulin.

a.Immunoglobulins ‑ These are large complex protein

molecules that belong to that class
of plasma proteins known as gamma globulins.Gamma globulin, antibody, and immunoglobulin all mean the same
thing.Immunoglobulins are synthesized
by B‑cells after stimulation by an antigen, and are specific for that
antigen.

b.Structure of immunoglobulins ‑ Each immunoglobulin is

composed of four polypeptide
chains.

(l)Two of the chains are large and termed heavy (H)

chains.

(2)Two of the chains are small and
termed light (L)

chains.

(3)Both the heavy and light chains have a constant

region and a variable
region.The constant regions are the
same for all heavy chains within a given

immunoglobulin class, and the
same is true for light chains.The
variable regions are unique for each immunoglobulin type and give them their
specificity.

c.Classification of immunoglobulins ‑Immunoglobulins are

divided into five classes based
upon the constant region

of the heavy chain.Within each class, the constant region of
every heavy chain is identical.The
classes are as follows.

(l)IgG (Immunoglobulin G) ‑ The most abundant in the

body.It circulates in the blood and can cross the

placenta.

(2)IgM ‑ This is another circulating immunoglobulin,

but it is present in much lower
quantities than IgG.

IgM
also serves as an antigen receptor on the surface of B cells.

(3)IgA ‑ Secreted on the surfaces of the body that open

to
the outside.Found in tears, saliva,
and other

surface secretions.

(4)IgD ‑ Found attached to the surface of B‑cells where

it
serves as an antigen receptor.

(5)IgE ‑ A non‑circulating antibody.It attaches to

Mast cells in the tissues and
mediates allergic

responses.

d.Antibody
diversity - Clonal selection - It was pointed out earlier that each
lymphocyte had a unique antigen receptor. As noted above the antigen receptor
for B cells are IgD and IgM antibodies attached the surface of the cell
membrane.How is it possible for each
lymphocyte to have a uniquely shaped antigen receptor and be able to produce an
antibody that is exactly the same shape?

(1)During
development of a lymphocyte there are about 200 or so gene segments that code
for antibody and antigen receptors.During the maturation of the lymphocyte, the variable regions are
assembled randomly by "mixing and matching" various gene
segments.With several hundred
fragments to choose from, right away it becomes obvious that millions of
possible amino acid sequences in the final antibody are possible.

(2)The
different variable regions for both light chains and heavy chains are not
attached randomly to the different constant regions which also increases
variability.

(3)The
genes for B-cell receptors and antibodies show hypermutability.They mutate very rapidly during development
increasing thepossible receptor types
even further.

(4)Once
an antigen finds a receptor it fits, the lymphocyte which bears that receptor
has been "selected."With
appropriate costimulation it will rapidly divide forming a clone of identical
cells which are also sensitive to the same antigen.In the case of B-cells this clone becomes a clone of antibody
secreting cells all of which produce antibody specific for the antigen which
did the selecting.

e.Functions
of immunoglobulins - Ig usually does not destroy antigen directly.Usually they mark antigen for
destruction by other agents of the defense system such as phagocytic cells or
complement.The principal functions
that immunoglobulins are involved in are as follows.

(l)Precipitation
 Soluble molecules (mostly proteins) such as bacterial toxins are precipitated
out of solution into masses which can then be phagocytized.Such molecules are sometimes called
anti-toxins and preciptins.IgG

(5)Neutralization‑ These
react with viruses andbacterial
exotoxins by destroying their ability to infect cells.IgG and IgA.

(6)Lysins‑These immunoglobulins causethebreakup

of
cells.They dothisbytargetingthecellswith complement
proteins.The complement proteins then
react onthe surface of the cell
causing holes toappear in the
membrane.The complement proteins may
be thought of as a bomb.The bomb is
placed on the target cell and then activated by immunoglobulin.

IgG and IgM.

f.Complement ‑This is a
major mediator of HMI.It

consists a number ofdifferentplasma proteins.When
immunoglobulin reacts with antigen it often initiates aseriesof complement reactions.These
reactions are usually termed the "fixation" of complement.Once the complement begins to react it can
mediate a number of different processes.These include:

(l)Lysis or destruction of cells by
destroying

their membranes.

(2)Toxin inactivation.

(3)Initiation of inflammation.

(4)Opsonization

(5)Enhancement of immunoglobulin formation.

(6)Stimulation of B‑cell lymphokine production.

7.Cell mediated immunity ‑ In CMI, not only is the effector

always acell,but the target is
also a cell.The target cell may be
one of the following.

a.A host cell that contains an intercellular parasite (TB

is an example.

b.A transformed cell (one with new antigens) due either

toa virus infection or the cell has become cancerous.

c.A foreign tissue graft.

The target cell is always killed by
either contact with a

T‑cell, macrophage, or NK
cell.The sequence of events in a CMI
response is as follows.

a.An
APC recognizes the target cell antigen and processes it. This information is
communicated to a helper T-cell combined with the MHC class II protein of the
APC.The antigen is also presented
directly to a cytotoxic T cell by the target cell itself combined with its MHC
class I protein.

b.The helper T‑cells then release a seriesof lymphokines

thathave the following effects.

(l)Macrophages
are attracted to the antigen bearing

cells, inhibitedfrom leaving the area,and then

activated so that they become
more phagocytic. These activated macrophages destroy the target cells.

(2)The cytotoxic T‑cells which were directly activated by the
antigen are stimulated to proliferate (by

Il‑2).These then attach to the antigen bearing
cells which they destroy.

(3) NK cells are activated.

c.Memory
T cells remain following the immune response.

d.Becausethe entire CMI response
is mediated by white

cells, all CMI responses have an
inflammatory appearance about them.

8.Tolerance
‑ The immune system normally recognizes selfand does not attack its own body.This is known as tolerance.The following mechanisms seem to play a role in inducing tolerance.

a.Negative
selection - During differentiation, any lymphocyte which has an antigen receptor
that will react with body antigens is destroyed.This appears to be the major mechanism of tolerance.

b.T
suppressor cells seem to play some type of role in tolerance, but exactly what
that role is and how important it may be are not known.

c.Anergy
may also play a role in inducing tolerance.Whenever an antigen combines with a lymphocyte and there is not
costimulation, the lymphocyte may permanently lose its ability to respond,
thereby inducing tolerance to that antigen.

d. Besidesnormalselftolerance,there isaspecial

case wherebythebody tolerates foreign antigens.This is the caseof the mother's
immune system accepting afetus which
bears some of its father's antigens.

D.Immunity against disease ‑ Immunity
against disease causing

organisms is obtained by exposure to these
organisms, or at least some of their antigens.Once an immune response has been mounted against a particular
antigen, memory cells will remain, and if that antigen is again encountered,
and immediate and overwhelming immune response willbelaunched,preventingthe organismfromestablishing an infection.Immunity can be of two types.

l.Natural ‑ Here immunity is developed by exposure to organisms

by
natural means.Sometimes the actual
disease will be seen but low level exposure can provide immunity with no overt
symptoms.

2.Artificial ‑ This is vaccination.Deliberate injection of

small amounts of antigen stimulate the
immune system andprovide for
immunitywhichwill protect against exposureto the organism under normal conditions.

E.Organ transplantation ‑ During the
last thirty years the idea of

replacing defective organs surgically with
healthy ones taken

from a donor has become a viable means of
treatment.Most failure is due to
rejection by the immune system.

1. Tissues
from donors and recipients will have different HLA (MHC) and consequently the
CMI division will mount an attack.

2.In a mismatched graft, normally the graft will take and grow

for the first few days.Vascularization of the graft will
begin.On days 5 through 7 a massive
cellular infiltration of the graft tissues begins.The majority of the infiltrating cells are cytotoxic T cells and
macrophages.Following this

infiltration, necrosis of the grafted
tissues begins and within a few days the graft is completely rejected.

3.Prevention of graft rejection involves tissue matching such

that the HLA's of both donor and
recipient and as similar as

possible.An antigen match up of about 75% is considered minimum.

4.Even with the best tissue matching usually some suppression

of the recipient's immune system is
necessary.Various drugs

and anti‑lymphocyte sera are used
for this purpose.

F.Autoimmune disease ‑ This is
where the immune system begins

reactions against self antigens.The cells involved are usually cytotoxic T
cells.There are several different
causes for these reactions.

l.New or altered antigens may appear on the surface of body

cells.These will be treated as foreign by the immune system.

2.Foreign antigens which are very similar to self antigens maystimulate an immune response (HMI or
CMI).The immune

effectors then cross react with the
similar self antigens.By way of
example streptococcal species can induce antibodies that will cross react with
antigen on the heart producing rheumatic heartdisease.

3.Certain body antigens (such as those in the lens of the eye)

are sequestered from the immune system
since before birth.If exposed at a
later date they will stimulate an immune

response.Cataracts of the eye are thought to be such a response.

4.It is also possible that a deficiency of T suppressor cells

may lead to immune responses against
self antigens.

G.Allergic responses (hypersensitivities)
‑These can be thought ofas over reactions of the immune
system.There are two typesof responses based upon the two types
of immunity.

l.Immediatehypersensitivity‑Thisisallergymediated

by
immunoglobulin.The sequence of events
is as follows.

a.Exposure to antigen causes the synthesis of IgE.

b.IgE does not circulate but rather attaches to Mast cells

and basophils.

c.A subsequent exposure to the antigen results in an

antigen‑antibody response
occurring on the surface of these cells.This causes them to release chemical substances such as histamine and
heparin which affect the circulatory system and the excitable tissues.

d.The manifestations of the allergic response depend upon

which part of the body the reaction
occurs in. These types of reactions are often referred to as anaphylaxis.

e.Anaphylactic shock ‑ This is a highly acute and generalized

allergic response that affects most
of the tissues of the body.There is
massive vasodilation and loss of fluid from the circulatory system.The edema that results can block the
respiratory passages causing rapid death.If this does not occur, cardiac shock can result and this too will
result in death.Anaphylaxis is life
threatening and must be treated immediately.It is usually countered by giving vasoconstrictive agents such as
epinephrine which will also open the respiratory passages.

2.Delayed
hypersensitivity ‑Although this
is classically referred to as a "hypersensitivity" is really just a
CMI response.As it is mediated by T
cells known as T delayedhypersensitivity
cells (TD).These cells may
display either the CD4 or CD8 markers.The sensitized cells release cytokines such as gamma interferon that
attract and activate macrophages. Macrophages then clear the antigen.The reactions require 24 to 72 hours to
appear following exposure.This is
because it takes this period of time for the appropriate cells to congregate in
large enough numbers to form a visible response. Poison ivy is a classic
example as is the tuberculin test.

H.Tumor immunology - Cancer cells frequently
have changed surface components (antigens).This is the basis of recognition by the immune system.Once recognized both antibody reactions and
cellular reactions can destroy the tumor cells.

1.Antibody
mediated reactions include the following.

a.Lysis
by antibody and complement.

b.Phagocytosis
of opsonisized cells.

c.Antibody
mediated loss of adhesive properties of tumor cells.Many kind of tumor cells must adhere to one another or to two
other tissues in order to metastatic.Antibodies which prevent this prevent metastasis.